tbuckley/cabot-search huggingface dataset:
BOS-371, a monoclonal antibody against IL1RAP: Characterization in preclinical models of AML.
Authors: Kip A West, Sanjay Kumar, Martin Scott, John G Emery, Ulrich G Steidl, Swathi-Rao Narayanagari, Kelly Mitchell, Fang Ren, Hua Ying, Qi Fei, Teddy Yang, Eric Svensson, Galit Rosen
Journal: Journal of Clinical Oncology (2023)

7030 Background: IL1 receptor accessory protein (IL1RAP) is a cell surface protein overexpressed on leukemia stem cells (LSC) and progenitors in AML, CML and high-risk MDS. It is an indispensable co-receptor for the IL1 superfamily, but its role reaches beyond anti-apoptotic pathways. IL1RAP directly interacts with and potentiates signaling of FLT3 and c-KIT which have significant roles in AML pathogenesis. High IL1RAP is correlated with poor prognosis and IL1 blockade attenuates expansion of LSCs. Thus, targeting IL1RAP has emerged as a promising immunotherapeutic approach for myeloid malignancies. BOS-371 is a humanized monoclonal antibody targeting IL1RAP that has been Fc-engineered to enhance its capacity to induce antibody directed cell cytotoxicity (ADCC) and deplete IL1RAP-expressing AML cells. Methods: The preclinical activity of BOS-371 was characterized using multiple assays. In vitro analysis included: binding affinity in IL1RAP-expressing cell lines; inhibition of IL1-dependent signaling as measured by IL1a -stimulated secretion of IL6 from MRC5 lung cancer cells; measurement of ADCC in co-cultures of human NK cells with either IL1RAP-expressing cell lines or primary AML cells; and cell growth by monitoring metabolic activity of primary AML cells. In vivo efficacy of BOS-371 was determined in AML models: MV4-11 and ML2 cells (CDX) implanted in NOG and NOD-SCID mice, respectively, and patient-derived (PDX) leukemia cells implanted in NOG mice. Results: BOS-371 binds with high affinity to IL1RAP-expressing cells (average EC50 337pM) leading to potent inhibition of IL1 signaling (IC50 600pM). Co-culture assays in the presence of BOS-371 showed potent induction of ADCC with an EC50 of 60-70pM (cell lines) or 4-11pM (primary cells) and 80-100% cell lysis (both cell lines and primary cells). The ability of BOS-371 to impact AML cell growth exclusively through inhibition of IL1 signaling was measured in a panel of 15 primary AML samples. Incubation with BOS-371 led to IC50s ranging from 20-700nM in responsive samples. Evaluation of BOS-371 activity in vivo showed that administration of BOS-371 resulted in significant anti-leukemic activity. In CDX studies, BOS-371 treatment led to &gt; 50% decrease in systemic disease and engraftment in bones and organs. The results observed in CDX AML models were reproduced in PDX mouse models of AML, where decreases in both peripheral ( &gt; 70%) and bone marrow ( &gt; 50%) disease burden in response to BOS-371 were observed. Conclusions: These findings demonstrate that BOS-371 binds with high affinity to IL1RAP, potently inhibits IL1 signaling and induces ADCC, leading to anti-leukemic activity in vitro and in vivo. The preclinical results support the clinical investigation of BOS-371 for the treatment of myeloid malignancies. A Phase 1 trial is currently in development.
Correlation between MSI, TMB, and TGFBR2 gene mutation in solid tumors.
Authors: Xinglong Fan, Huimin Hu, Yufeng Cao, Tiantian Xuan, Jianjun Xin, Qiangfang Gao, Juan Ma, Chenxi Wang, Ran Ding, Fanfeng Bu
Journal: Journal of Clinical Oncology (2023)

e14558 Background: TGFBR2 encodes a receptor kinase which signals to downstream effectors in the TGF-ß signaling pathway. Recent research has shown that truncation mutations of TGFBR2 in gastric cancer with high tumor mutational burden. However, the relationship remains unclear in other solid tumors. Methods: We retrospectively analyzed the TGFBR2 mutations of 19370 Chinese patients with pan-cancer during 2019-2022 (Simcere Diagnosis, Nanjing, China) Next-generation sequencing (NGS) assessed somatic mutations in tumor tissue. We figured out TGFBR2 mutation frequency, TMB and MSI in TGFBR2-mutant, TGFBR2 wild-type. Results: We have detected TGFBR2 mutants in 536 (2.8%) samples. The top 5 frequent cancers were colorectal cancer (132, 24.7%), lung cancer (118, 22%), gastric cancer (78, 14.5%), biliary tract tumors(52, 9.7%) liver cancer (33, 6.2%).TGFBR2 variants included missense/indel/insert (238, 44.4%), truncation (219, 40.9%), splicing site variant (23, 4.3%), and CNV (33, 6.2%).The inactive variants include missense, which occurs in the TGFBR2 serine/threonine kinase domain, truncation and splicing site variant. However, truncation was the most common type, recurring in a few hot spots (p.K153Sfs*35, p.K153Afs*3, p.R520* ). And we found that the TMB and MSI in the TGFBR2 mutation group was significantly higher than that in the TGFBR2 wild-type group [TMB-H (TMB ≥10 musts/Mb): TGFBR2-MUT vs TGFBR2-WT, 41.2% vs 9.5%, p &lt; 0.01; MSI-H: TGFBR2-MUT vsTGFBR2-WT, 27.4% vs1.7% p &lt; 0.01]. In the TGFBR2 mutation group, It was also observed that TMB and MSI in the TGFBR2 truncation or splicing site mutant (INACT) group was significantly higher than that in the other mutant types (VUS) group [TMB-H (TMB ≥10 musts/Mb): TGFBR2-INACT vs TGFBR2-VUS, 51.0% vs 27.9%, p &lt; 0.01; MSI-H: TGFBR2-INACT vs TGFBR2-VUS 39.4% vs 10.6% p &lt; 0.01]. And then, we separately analyzed the correlation between MSI, TMB and TGFBR2 gene mutation in the top 5 frequent cancers. Over 60% of patients with TGFBR2 mutations in colorectal cancers have high TMB and MSI values [TMB-H (TMB ≥10 musts/Mb): TGFBR2-MUT vs TGFBR2-WT, 71.3% vs 12.8%, p &lt; 0.01; MSI-H: TGFBR2-MUT vs TGFBR2-WT, 61.2% vs 3.0% p &lt; 0.01]. Conclusions: We analyzed the distribution of TGFBR2 mutants in Chinese patients with solid tumors. Our data showed that TGFBR2 mutant was significantly associated with TMB-H and MSI-H, and this may be a potential molecular marker of immunotherapy. And studies have shown that the combination of TGF-β inhibitors and immune checkpoint inhibitors can increase the killing effect of T cells on tumors. In short, detection of TGFBR2 mutation has certain clinical significance.
Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).
Authors: Munaf Alkadimi, Maria Elena Fierro, Lauren Diaz Boyle, Kana Lucero, Kathleen Franklin, Michael Mader, Zohra Nooruddin
Journal: Journal of Clinical Oncology (2023)

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG &lt; 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]
The influence of grade on mortality risk in salivary gland malignancy.
Authors: Amanda J Bastien, Michael Luu, Bonnie Balzer, Katri Aro, Julie Jang, Alain C. Mita, Kevin Scher, Jon Mallen-St. Clair, Missael Vasquez, Joel Epstein, De-Chen J Lin, Michelle Chen, Zachary Stephan Zumsteg, Allen S. Ho
Journal: Journal of Clinical Oncology (2023)

e18100 Background: Salivary malignancies are amongst one of the most difficult malignancies to classify.Currently, the impact of histologic variants has not been well described. The objective of this study was to evaluate histologic subtype and grade in salivary cancer staging. Methods: Salivary cancer histologies were collected from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable models were used to adjust for clinicopathologic covariates and assess for relationships between histologic subtype, grade, and survival. Results: Histologic variants have a wide range of mortality risk (e.g., acinic cell carcinoma has a favorable 5-year survival, in opposition to salivary duct carcinoma) on univariate analysis(p &lt; 0.001). Using multivariable analysis, the survival differences disappeared. However, worsening grade corresponded signficantly with deteriorating survival (5-year OS of 89% [95% CI 88-90%] (low-grade), 81% [95% CI 79-82%] (intermediate-grade), 45% [95% CI 44-47%] (high-grade) (p &lt; 0.001)), on both multivariable analysis and propensity score matching. Recursive partitioning analysis incorporating grade into current staging generated a TNM+G schema (c-index 0.75, 95% CI 0.745-0.755) superior to the existing system (c-index 0.73, 95% CI 0.723-0.736). Conclusions: Grade is a significant factor in determining mortality risk in salivary cancers. Including grade into staging will improve current staging systems.
Impact of social determinants of health (SDOH) measures on prescribing advanced androgen blockade (AAB) in patients with metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Rahul Ravilla, Thomas Wilson, Chuck Wentworth, Sudha Sundarrajan, Janet L. Espirito, Nicholas J. Robert
Journal: Journal of Clinical Oncology (2023)

e17086 Background: Use of AAB (abiraterone acetate, apalutamide or enzalutamide) has been shown to improve survival in mHSPC, but many patients are not prescribed this treatment. There is substantial interest in the broader role of SDOH in cancer. We explored how SDOH influences prescribing patterns of AAB in patients with mHSPC. Methods: Patients diagnosed with mHSPC between 1/1/2017 and 12/31/2021 were identified using the iKnowMed electronic health record database from The US Oncology Network of community oncology practices. Records were searched for prescriptions for AAB (based on intent to treat). Individual level measures were age, diagnosis year, ECOG, race and type of health insurance. Area level measures were Area Deprivation Index (ADI) at national and state level, and rural status. ADI is a validated metric based on demographic variables from census block groups; high ADI scores for state ( &gt; 8) and national ( &gt; 80) level are markers of low socioeconomic status. Logistic regression models were run on each SDOH variable and adjusted for confounding variables, including a joint distribution model of African American (AA) and ADI (significance at p &lt; 0.05). Results: There were 3,855 patients identified with mHSPC: 40% had a prescription for AAB. Summary measures overall were mean age: 71 years, AA: 10%, Medicaid: 5%, ECOG 0-1 and 2+: 60% and 14% respectively; and diagnosis year 2017-21: 15%, 20%, 21%, 22%, and 21% respectively. Area level scores: National ADI high: 8%, State ADI high: 18%, rural: 5%. Interaction variable: AA + State ADI (high): 2%. Statistical differences between those with/without AAB (not shown) were diagnosis year, ECOG and age. Multivariate logistic models were adjusted for these 3 variables with the single SDOH measure as the primary independent variable and the binary variable AAB as the dependent variable (Table). Conclusions: There was no significant association between AAB prescriptions and AA race, rural status, ADI (state or national), or Medicaid status. These data indicate that SDOH measures do not appear to influence prescribing of these treatments. We believe this study is among the first to examine these particular SDOH measures and their relationship to the prescribing of oncology treatments. Further research should be conducted into the impact of SDOH measures on the fulfillment and compliance of these drugs. [Table: see text]
Genomic characterization of somatic mutations by race and ethnicity in pancreatic cancer defined through AACR project GENIE.
Authors: J. Alberto Maldonado, Chin-Hsien Tai, Christine Alewine
Journal: Journal of Clinical Oncology (2023)

4138 Background: KRAS, TP53, SMAD4, and CDKN2A are widely recognized as the most common somatic mutations amongst patients with pancreatic ductal adenocarcinoma (PDAC); however, previous genomic studies have disproportionately included non-Hispanic White (NHW) patients with little to no inclusion of racial and ethnic minorities, particularly non-Hispanic Black (NHB) and Hispanic patients. Additionally, little is known about the distribution of KRAS point mutations in PDAC in specific racial and ethnic groups. Here, we describe somatic mutation differences in a larger and more racially and ethnically representative PDAC cohort than previously characterized. Methods: PDAC mutational data was downloaded from AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) v13.0, an international data registry of sequenced tumor samples from nearly 150,000 patients, on cBioPortal. PDAC cancer type was identified using OncoTree code. NHW, NHB, Hispanic (of any race), and Asian patients were then selected. Mutational frequency was calculated for all mutations. The primary objective was to compare the mutation frequencies between NHW and other races with respect to the most common mutations. To maximize power, we included any mutation with a frequency ≥5.0% where testing for mutation of that gene had been performed in at least 150 patients. Specific point mutations in KRAS were also extracted with stratification for racial and ethnic group. Fisher’s Exact Test was used to calculate the statistical significance of the differences in mutation frequency between NHW and minority groups. Results: Patients in the PDAC cohort included 5,292 individuals (NHW N = 4296, 80.7%; NHB N = 264, 5.0%; Hispanic N = 460, 8.7%; Asian N = 299, 5.7%). As compared to the NHW group, NHB patients had higher rates of TP53 (78.7% vs 69.0%, P = 0.0006) and PTPRT (5.3% vs 1.8%, P = 0.0095) mutations but fewer GNAS (0.4% vs 2.8%, P = 0.0097) mutations while Asian patients had higher frequency of ARID1A mutations (13.0% vs 8.8%, P = 0.024). KRAS G12D mutation was more prevalent in Hispanic patients (47.0% Hispanic vs 41.1% NHW, P = 0.0238), although rate of KRAS mutation overall was the same. Prevalence of KRAS G12C mutation was equivalent amongst all groups with an overall 1.6% frequency. Conclusions: Understanding the genomic landscape of PDAC is critical as we move towards increased use of targeted therapies to treat this disease. In this study, TP53, PTPRT, GNAS, and ARID1A mutations were shown to occur at different frequencies in specific racial and ethnic groups. G12D mutation of KRAS was disproportionately increased in Hispanics. These differences in molecular landscape amongst racial and ethnic groups could contribute to precision medicine strategies used to address this deadly disease.
Healthcare resource utilization (HCRU) and costs among adult patients with lung cancer with broad panel genomic testing and clinically relevant or non-clinically relevant genomic variants.
Authors: Kristin Moore, Brandon Diessner, Lisa Le, Tze-An Yuan, Feng Cao, Thomas Horstman, Christina Landis, Michael P Johnson, Amy Sainski-Nguyen
Journal: Journal of Clinical Oncology (2023)

e18889 Background: Lung cancer is the second most common cancer diagnosed in the United States. An estimated 236,740 new cases of lung cancer were diagnosed in 2022. Use of genomic testing to drive treatment decisions can lead to improvements in patient survival. However, the HCRU and costs of genomic testing are just being understood and little is known about the impact of the clinical relevance of those genomic findings. Methods: This retrospective analysis utilized administrative claims and enrollment information with linked genomic sequencing results from Optum’s de-identified Market Clarity Data and Clinicogenomics Database. Adult lung cancer patients newly diagnosed between 01 January 2016 – 30 June 2021 with evidence of treatment and genomic sequencing results post diagnosis were eligible for the study. Patients were required to have at least 6 months of continuous enrollment prior to and after their diagnosis date, unless death occurred, and were followed until death, disenrollment, or study end. Cohorts were created based on presence of clinically relevant variants with an FDA-approved treatment for lung cancer. Unadjusted all-cause HCRU and costs during follow-up were reported as per-patient per-month (PPPM). Results: This study identified 2,190 patients, of which 999 (45.6%) had clinically relevant variants. Age, insurance type, and geographic region did not appear to differ substantially between groups, though those with clinically relevant variants were more likely to be female (57.4% vs. 46.0%). During follow-up, the average number of PPPM ambulatory visits was similar between groups (5.89 vs. 5.58, p = 0.08), but the average number of emergency room visits (0.29 vs. 0.23, p &lt; 0.01) and inpatient stays (0.12 vs. 0.11, p = 0.03) were higher among those with clinically relevant variants. Additionally, those with clinically relevant variants had higher average PPPM all-cause medical costs ($20,948 vs. $19,097; p = 0.02) and pharmacy costs ($3,073 vs. $2,083, p = 0.02). Conclusions: Average PPPM emergency room visits, inpatient stays, medical costs and pharmacy costs were higher among lung cancer patients with clinically relevant variants compared to those with non-clinically relevant variants. Future research should evaluate HCRU and costs attributable to targeted therapy. [Table: see text]
Retrospective analysis of NUT carcinoma: The Northwestern experience.
Authors: Anthony V. Serritella, Farres Obeidin, Yanis Boumber, Jyoti D. Patel, Haimin Li, Rui Yi, Jochen H. Lorch
Journal: Journal of Clinical Oncology (2023)

e18096 Background: NUT carcinoma (NC) is a rare, highly aggressive carcinoma that originates from a wide variety of organs, typically presenting as poorly differentiated squamous cell carcinoma. Cases typically are aggressive, with a median overall survival (OS) of only 6.5 months. Given only 40-50 cases are diagnosed in the United States annually, NC is an orphan disease with no standard treatment options and the outlook is generally poor. A previously published case of thyroid NUT carcinoma demonstrated a prolonged response to pembrolizumab for &gt; 3 years. Methods: Patients (pts) harboring NUTM1 rearrangements were retrospectively identified at our institution. We reviewed characteristics related to tumor immune microenvironments by tumor immunohistochemistry and next generation sequencing as well as clinical outcomes. Results: 10 NMC pts were identified (5 female, 5 male): lung (6), thyroid (2), primary mediastinal (1), maxillary sinus (1). The median age at diagnosis was 49 years (range of 27-75). The thyroid cases were diagnosed at ages 51 and 75. 8/10 had metastatic or unresectable disease at diagnosis, 3 of which with central nervous system metastases. In 8 evaluable patients, NUTM1 rearrangements included BRD2 (1), BRD3 (1), BRD4 (2), NSD3 (3), SCL12A6 (1). Median OS was 10.8 months (range 1.1-75.8m); 3/10 patients were deceased. 3 patients received IO (2 ipilimumab/nivolumab, 1 pembrolizumab) after either surgery, RT, or chemotherapy combined with RT. Patients who received IO had a median survival of 18 months (range 10.9-76.0 months) compared with 8.5 months in the 8 patients not receiving IO (p = 0.07). All patients with tissue available in this cohort all had PD-L1 staining &lt; 5%, were microsatellite stable (MSS) and had a low median tumor mutation burden (TMB) of 3.1 mut/Mb. Conclusions: In our series, NC originating from the thyroid gland accounted for more cases than expected, thyroid NC patients were older than NC cases arising in other locations and with the more typical squamous histology. Despite relatively low PD-L1 staining, TMB, and MS status, our data suggests NMC tumors may be amenable to treatment with immune checkpoint inhibitors, warranting further investigation.